This is a clinical and laboratory program designed to study the mechanism of cell mediated immunity (CMI) and how it is subverted in leprosy. In particular we will define the role of key cytokines in regulating the mechanisms necessary to mount a protective response to M. leprae infection. For this purpose we will examine the phenotypic and functional characteristics of T cells, monocytes and NK/LAK cells in the blood and after migration into the lesions as well as resident endothelial cells, Langerhans cells and keratinocytes. Using immunocytochemistry, election microscopy, cell proliferation, activation and cytotoxicity assays as well as Northern blotting, ELISA and quantitative PCR, we will evaluate the nature, interactions and secretory repertoire of cells which accumulate in lepromatous, tuberculoid and reactional patients skin. The ability of recombinant cytokines such as IL-2 and IFN-gamma to modify host cells function and dispose of M. leprae in situ will be compared with the generation and function of cytotoxic cells reactive against infected monocytes in vitro. The role of cytokines and leukocyte activation in the pathobiology of the reactional states including erythema nodosum leprosum and reversal reaction will be dissected. How cytokines including GM-CSF impact on tissue damage and wound healing in the skin of leprosy patients will be studied. And finally how the HIV-1 pandemic will affect the incidence and clinical progression of leprosy will be investigated. Each of these modalities will be followed temporally, in selected patient populations, obtained through collaborative efforts in Brazil and the Philippines. The work is an extension of the achievements reported in the prior grant period.